Active pharmaceutical ingredients (APIs) that are useful for treating respiratory diseases are generally formulated for administration by inhalation with portable inhalers. The two most popular classes of portable inhalers are pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs).
The vast majority of dry powder inhalers rely on the patient's inspiratory effort to fluidize and disperse the drug particles. In order for the drug to be effectively deposited in the lungs, it is generally accepted that the aerodynamic diameter of the particles must be between 1 μm and 5 μm. As a result APIs are typically micronised to achieve fine particles with a mass median diameter (as determined by laser diffraction) in this size range. Unfortunately fine micronised drug particles generally exhibit poor powder flow, fluidization and dispersion properties. Powder flow or “powder flowability” is the ability of a powder to flow. It is important with respect to metering of the drug particles into a unit dose, either from a reservoir or into pre-packaged unit dose containers (e.g., capsules or blisters). Powder fluidization, which is the mobilization of the powder into the airflow during a patient's inspiration, impacts the delivered dose from the inhaler. Finally, powder dispersion is the break-up of powder agglomerates to primary drug particles. Poor powder dispersion negatively impacts the aerodynamic particle size distribution, and ultimately the delivery of API(s) to the lungs.
Two approaches have been employed in currently marketed products to improve the flow, fluidization and dispersion of fine drug particles.
The first approach involves the controlled aggregation of the undiluted drug to form loosely adherent pellets. The aggregates are formed in rotating blenders with the resulting large particle size distribution providing the required flow properties needed for accurate metering and improved powder fluidization. In the TURBUHALER™ (Astra-Zeneca) device, dispersion of the aggregates occurs by turbulent mixing. The dispersion energy is sufficient under optimal inspiratory flow rates to overcome the interparticle cohesive forces holding the micronised particles together. Because the powder dispersion depends critically on the energy utilized to break up the aggregates, the aerosol performance of pelletized formulations generally exhibits a strong dependence on the patient's inspiratory flow rate. In one study, the total lung deposition for pelletized budesonide was 28% when patients were asked to breathe quickly through the TURBUHALER™ device, and 15% when they were asked to breathe more slowly through the TURBUHALER™ device (see Borgstrom L, Bondesson E, Moren F et al: Lung deposition of budesonide inhaled via TURBUHALER: a comparison with terbutaline sulphate in normal subjects, European Respiratory Journal, 1994, 7, 69-73).
The second approach utilises a binary ordered mixture comprising fine drug particles blended with coarse carrier particles. α-Lactose monohydrate has been employed most frequently as the carrier and typically has a particle size between 30 and 90 μm. In most dry powder formulations, drug particles are present in low concentrations, with a drug to carrier ratio of 1:67.5 (w/w), being typical. Micron-sized crystals exhibit forces of attraction, primarily dictated by van der Waals, electrostatic, and capillary forces which are affected by the size, shape, and chemical properties (e.g., surface energy) of the crystal. Unfortunately the adhesive forces between the drug crystals and the carrier are difficult to predict, and may differ for different drugs in a fixed dose combination. During inhalation the drug particles are dispersed from the surface of the carrier particles by the energy of the inspired air flow. The larger carrier particles impact primarily in the oropharynx (i.e. the area of the throat that is at the back of the mouth), whereas the small drug particles penetrate into the lungs.
A key requirement for blend uniformity in an ordered mixture is that the drug and carrier particles interact sufficiently to prevent segregation. Unfortunately, this may reduce pulmonary deposition of the drug, due to poor dispersion of the drug from the carrier. Mean lung deposition for drugs in ordered mixtures is typically 10-30% of the metered dose. The poor lung targeting observed in ordered mixtures results in high deposition in the oropharynx, and the potential for local side-effects, and increased variability. The high variability in lung delivery observed is the result of variability in inertial impaction within the oropharynx, which is a consequence of the powder properties and anatomical differences between subjects. The mean variability in lung dose for micronized drug particle blend formulations is typically between about 30% and 50% (see Olsson B, Borgstrom L: Oropharyngeal deposition of drug aerosols from inhalation products. Respiratory Drug Delivery, 2006, pages 175-182). This is exacerbated further when aerosol delivery is dependent on the patient's peak inspiratory flow rate.
The aforementioned issues become especially acute when formulating pharmaceutical products that contain two or more active ingredients in fixed dose combination.
This was illustrated in a recently published study by Taki et al, Respiratory Drug Delivery 2006, pages 655-657. The study measured the aerodynamic particle size distributions of the two active ingredients of SERETIDE™, namely salmeterol xinafoate (SX) and fluticasone propionate (FP), as a function of flow rate in an ANDERSEN™ cascade impactor (ACI). The two formulations of SERETIDE™ tested, S100 and S500, refer to differences in the strength of the inhaled corticosteroid (ICS) fluticasone propionate, i.e., 100 μg, and 500 μg. The dose of the long acting β2— agonist (LABA) salmeterol xinafoate was held constant at 72.5 μg. The aerodynamic particle size distribution (aPSD) differed significantly for the two active ingredients in the blend formulation (see Table 1). Moreover, the aPSD was dramatically different for the two formulations. Mass median aerodynamic diameters (MMAD) ranged from 1.8 μm to 3.6 μm, geometric standard deviations from 1.7 to 3.9. The ratio of the two active ingredients in the fine particle fraction (FPF<3 μm and FPF<5 μm also differed significantly at the two flow rates tested. Hence, the adhesive properties between the drugs and the carrier differed significantly for each active ingredient and between the formulations as well. The nominal ratio of SX/FP (w/w) in S100 is 0.725, and 0.145 in S500. The ratio of SX/FP in the fine particle dose differs significantly from the nominal ratio, generally enriched in the FP component. The SX/FP ratio varies from +3.5% to −28% of the nominal dose ratios with flow rate and blend ratio. The observed differences are probably the result of differences in the API particle size distribution and differences in the dose ratios that may result from inadequate mixing. Furthermore, one API may have lower affinity for the carrier, and may segregate in the formulation at any stage in the manufacturing process. Moisture uptake may also differ for the two APIs, leading to differences in agglomeration on storage. All of these factors taken in total dramatically increase the complexity of the development process, and the overall variability in drug delivery.
TABLE 1Aerodynamic particle size distributions of fixed dose combinations of salmeterolxinafoate and fluticasone propionate formulated as ordered mixtures with coarselactose monohydrate (Taki et al. Respiratory Drug Delivery 2006, pp. 655-657)Mean (n = 4)MMADFPF < 3 μmFPF < 5 μm(μm)GSD(%)(%)Q = 30 LPMS100SX3.61.910.318.2FP3.22.114.522.9t-test (p-value)0.0300.4400.0130.011SX vs. FPSX/FP0.52 (−28%)0.58 (−20%)(% from nominal)S500SX2.81.812.919.9FP2.71.817.325.9t-test (p-value)0.2500.4700.0150.005SX vs. FPSX/FP0.11 (−24%)0.11 (−24%)Q = 66 LPMS100SX1.92.522.026.9FP2.12.021.327.0t-test (p-value)0.0180.1700.3180.898SX vs. FPSX/FP 0.75 (+3.5%) 0.72 (−0.7%)S500SX1.83.917.621.3FP2.11.721.226.6t-test (p-value)0.3040.3700.0070.001SX vs. FPSX/FP0.12 (−17%)0.12 (−17%)
In order to circumvent the problem of the formulation of multiple active ingredients in a single blend, devices (e.g. the GEMINI device of WO 05/14089) are known which incorporate two separate blisters containing each independent drug blend, which is then actuated concurrently. While such device options for combination therapy may minimize potential interactions between the active ingredients and the device components, they do nothing to solve other inherent drug targeting and variability issues associated with lactose blends. Hence, a need exists for improved formulations which overcome the dosing issues associated with blends of multiple active ingredients, and which provide for improvements in dose consistency and lung targeting. The need is especially acute for APIs with vastly different physicochemical properties (e.g., solubility), where finding a common solvent for particle engineering is problematic.
It has now been found that inhalable dry powder formulations that contain two or more active ingredients and yet have desirable fluidization and dispersion properties of drug particles may be prepared by engineering the active ingredients within inhalable spray-dried particles.